Molecular nephrology: types of acute tubular injury

Abstract

The acute loss of kidney function has been diagnosed for many decades using the serum concentration of creatinine - a muscle metabolite that is an insensitive and non-specific marker of kidney function, but is now used for the very definition of acute kidney injury (AKI). Fortunately, myriad new tools have now been developed to better understand the relationship between acute tubular injury and elevation in serum creatinine (SCr). These tools include unbiased gene and protein expression analyses in kidney, urine and blood, the localization of specific gene transcripts in pathological biopsy samples by rapid in-situ RNA technology and single-cell RNA-sequencing analyses. However, this molecular approach to AKI has produced a series of unexpected problems, because the expression of specific kidney-derived molecules that are indicative of injury often do not correlate with SCr levels. This discrepancy between kidney injury markers and SCr level can be reconciled by the recognition that many separate subtypes of AKI exist, each with distinct patterning of molecular markers of tubular injury and SCr data. In this Review, we describe the weaknesses of isolated SCr-based diagnoses, the clinical and molecular subtyping of acute tubular injury, and the role of non-invasive biomarkers in clinical phenotyping. We propose a conceptual model that synthesizes molecular and physiological data along a time course spanning from acute cellular injury to organ failure.

Fig. 1 |. Rapid resolution of serum creatinine in most patients with AKI.

a | Our study of 61,726 patients who were admitted to the New York Presbyterian Hospital and met Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury (AKI) showed that serum creatinine (SCr) resolved rapidly in most patients: ~33% of events resolved within the first days of hospital admission, ~60% within 2 days and ~70% within 3 days. b | Assessment of the proportion of patients with electrolyte abnormalities, according to time to resolution of SCr shows that rapid resolvers (that is, those points on the left-side of the graph) were less likely to have electrolyte abnormalities than patients with sustained or unremitting elevation of SCr levels (those on the right-side of the graph). In both a and b, the difference between two points along the x-axis represents a period of 24 h. Data are taken from Xu et al..

Fig. 2 |. Renal expression of NGAL mRNA.

In situ hybridization of an ischaemic human kidney explanted by nephrectomy shows NGAL expression primarily in distal segments of the nephron. Proximal tubules (PT, large crosssectional profiles) are negative. This patterning is similar to that seen in ischaemic mouse kidneys^,.

Fig. 3 |. Sources of AKI biomarker mRNA and protein.

mRNAs encoding KIM1, L-FABP and IL18 are transcribed in the proximal tubule (pink boxes, italics), whereas NGAL mRNA is synthesized primarily in the thick ascending limb and collecting duct. The protein products (blue boxes) are detected primarily at the sites of mRNA transcription, but may also be derived from the systemic circulation. The primary source of IGFBP7 and TIMP2 mRNA is unclear, since these genes and their protein products may be expressed ubiquitously within and outside the kidney. Plasma NGAL is freely filtered and largely reabsorbed by the proximal tubule by megalin-dependent pathways, and may be multimeric. Kidney-derived NGAL is monomeric.

Fig. 4 |. Biomarkers change the definition of AKI.

Different stimuli (for example, coronary ischaemia, sepsis or volume depletion) activate different biological pathways in the heart and kidney. The pathways begin with stimulus-dependent cellular responses, which may result in cell damage and subsequently organ damage, if and when the stimulus is sufficiently severe. In the most severe cases of ‘organ damage’, ‘organ failure’ occurs. Cellular responses and damage can be detected by biomarkers, but organ failure is currently estimated through the use of functional tests such as an echocardiogram (in the context of heart failure) or serum creatinine (SCr; in the context of kidney injury). Detection of biomarkers without evidence of organ failure represents a milder form of damage (or one detected early in its course) than detection of biomarkers together with evidence of organ failure. Note that radically different therapies apply to these three examples. Also note that volume depletion and ischaemia do not induce the same damage markers: >100 different markers of ischaemic damage are not upregulated by volume depletion, and hence metrics of cell damage, if actually present in volume depletion, are not yet established. EKG, electrocardiogram.

Fig. 5 |. Combined analysis of biomarker, serum creatinine and urine output for the assessment of kidney injury.

Biomarkers serve as ‘injury markers’ of the tubule, providing data regarding cellular injury and responses to noxious stimuli. Rising serum creatinine (SCr) on the other hand is a ‘functional marker’, indicative of excretory dysfunction. a | An insult leads to cellular damage, which can be detected by urine biomarkers. If insufficient numbers of nephrons are injured to cause organ dysfunction, no rise in SCr will be detected. b | An insult leads to cellular damage, which can be detected by urine biomarkers. If nephron injury is sufficient to cause organ dysfunction, a rise in SCr is detected. c | The absence of urine biomarkers and a normal SCr indicates that no cellular injury has occurred and that the kidney is not challenged by haemodynamic failure. d | Excretory dysfunction can occur without biomarker evidence of tubular injury. A rising SCr is indicative of excretory dysfunction, whereas the absence of urine biomarkers indicates sparing of tubular cells, a scenario that challenges the specificity of SCr as a marker of injury. This scenario is common in cases of volume depletion, diuretic use, and mild forms of heart or liver failure. AKI, acute kidney injury (defined according to SCr-based KDIGO Guidelines); CHF, congestive heart failure.